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Frailty Markers Comprise Blood Metabolites Involved in Antioxidation, Cognition, and Mobility

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Frailty Markers Comprise Blood Metabolites Involved in Antioxidation, Cognition, and Mobility Frailty markers comprise blood metabolites involved in antioxidation, cognition, and mobility Masahiro Kamedaa, Takayuki Teruyab, Mitsuhiro Yanagidab,1, and Hiroshi Kondoha,1 aGeriatric Unit, Graduate School of Medicine, Kyoto University, Sakyo-ku, 606-8507 Kyoto, Japan; and bG0 Cell Unit, Okinawa Institute of Science and Technology Graduate University, Onna-son, 904-0495 Okinawa, Japan Contributed by Mitsuhiro Yanagida, March 3, 2020 (sent for review December 2, 2019; reviewed by Hidenori Arai and Elizabeth H. Blackburn) As human society ages globally, age-related disorders are becom- aging) is affected not only by age, but also by disease, psycho- ing increasingly common. Due to decreasing physiological reserves physiological condition, and lifestyle (7, 8). and increasing organ system dysfunction associated with age, Metabolomics, a tool for evaluating metabolite profiles, em- frailty affects many elderly people, compromising their ability to ploys liquid chromatography–mass spectrometry (LC-MS) to cope with acute stressors. Frail elderly people commonly manifest reveal complex but highly integrated biological processes (5). complex clinical symptoms, including cognitive dysfunction, hypo- Although noncellular components (serum or plasma) of blood mobility, and impaired daily activity, the metabolic basis of which have most often been used for metabolomic assays (5), we de- remains poorly understood. We applied untargeted, comprehen- veloped whole blood and red blood cell metabolomics (9) to sive LC-MS metabolomic analysis to human blood from 19 frail and comprehensively investigate metabolic foundations of human nonfrail elderly patients who were clinically evaluated using the aging. Metabolomic analyses enable us to detect metabolites Edmonton Frail Scale, the MoCA-J for cognition, and the TUG for related to amino acid metabolism, the tricarboxylic acid (TCA) mobility. Among 131 metabolites assayed, we identified 22 cycle, nitrogen, sugar, purine/pyrimidine, lipid metabolism, markers for frailty, cognition, and hypomobility, most of which antioxidation, energy supply, and diet. were abundant in blood. Frailty markers included 5 of 6 markers Based on these quantitative, reproducible analytical methods, specifically related to cognition and 6 of 12 markers associated we recently reported 14 age-related metabolites relevant to with hypomobility. These overlapping sets of markers included antioxidative defense and nitrogen metabolism (10). Four recent metabolites related to antioxidation, muscle or nitrogen metabo- reports drew divergent, nonoverlapping conclusions (11–14), lism, and amino acids, most of which are decreased in frail elderly stemming from different experimental designs. For example, the MEDICAL SCIENCES people. Five frailty-related metabolites that decreased—1,5-anhy- former two reports applied the Fried CHS index as a diagnostic droglucitol, acetyl-carnosine, ophthalmic acid, leucine, and isoleu- tool, efficiently detecting hypomobility but offering no cognitive cine—have been previously reported as markers of aging, assessment (2), while the latter two used a 70-item clinical Frailty providing a metabolic link between human aging and frailty. Index focusing mainly on activities of daily living (ADL) as- Our findings clearly indicate that metabolite profiles efficiently sessment (15). Here we report the untargeted metabolomic distinguish frailty from nonfrailty. Importantly, the antioxidant ergothioneine, which decreases in frailty, is neuroprotective. Oxi- Significance dative stress resulting from diminished antioxidant levels could be a key vulnerability for the pathogenesis of frailty, exacerbating illnesses related to human aging. Frailty resulting from age-related deterioration of multiple or- gan systems displays complex features, including cognitive dysfunction, hypomobility, and impaired daily activity. How- frailty | antioxidants | cognitive impairment | metabolomics | aging marker ever, metabolic aspects of frailty remain unclear. We per- formed untargeted, comprehensive metabolomics of whole uman society is aging globally, in developed as well as in blood from 19 frail and nonfrail elderly patients. We identified Hdeveloping countries, and people over age 85 now constitute 22 markers, including 15 for frailty, 6 for cognition, and 12 for 1.6% of the world population. While life expectancy is in- hypomobility, most of which are abundant in blood. Frailty creasing, there is also an alarming rise in the number of frail markers include 5 of 6 for cognition and 6 of 12 for hypo- people who are predisposed to be bedridden and to require mobility. These overlapping markers include decreased levels nursing care. The prevalence of frailty among those aged 65 and of metabolites related to antioxidation, nitrogen, and amino over is estimated at 17%, or approximately 120 million individ- acid metabolism. Ergothioneine, an antioxidant involved in uals worldwide (1). Frail people suffer not only from physical neuronal diseases, declines in frailty. Thus, we reveal essential disabilities, but also from psychophysiological and social prob- metabolites linked to the pathogenesis of frailty, including lems (2), and thus require more social resources than healthy vulnerability to oxidative stress. peers. Frailty compromises their ability to cope with acute Author contributions: M.Y. and H.K. designed research; M.K., T.T., M.Y., and H.K. per- stressors due to declining physiological reserves and organ sys- formed research; M.K. and T.T. analyzed data; and M.K., T.T., M.Y., and H.K. wrote tem function (2, 3), although it has been suggested that frailty the paper. may be reversible (4). Moreover, human aging is a highly com- Reviewers: H.A., National Center for Geriatrics and Gerontology; and E.H.B., University of plex biological process exhibiting great individual variation, and California San Francisco Medical Center. until now, its metabolic basis has been little understood. The authors declare no competing interest. Because all tissues and organs are supplied by the circulatory This open access article is distributed under Creative Commons Attribution-NonCommercial- system, blood should reflect environmental conditions, genetic NoDerivatives License 4.0 (CC BY-NC-ND). and epigenetic factors, nutritional status, exposure to exogenous Data deposition: Raw LC-MS data in mzML format are available from the MetaboLights repository, http://www.ebi.ac.uk/metabolights/. substances, and lifestyle factors (5, 6). Therefore, human blood 1To whom correspondence may be addressed. Email: [email protected] or hkondoh@ samples are expected to document not only individual genetic kuhp.kyoto-u.ac.jp. variability, but also differences in physiological responses and This article contains supporting information online at https://www.pnas.org/lookup/suppl/ homeostatic mechanisms. For example, recent studies suggest doi:10.1073/pnas.1920795117/-/DCSupplemental. that in circulating leukocytes, telomere length (a biomarker of First published April 15, 2020. www.pnas.org/cgi/doi/10.1073/pnas.1920795117 PNAS | April 28, 2020 | vol. 117 | no. 17 | 9483–9489 Downloaded by guest on September 24, 2021 analysis of blood from frail and nonfrail elderly people. For mild cognitive impairment (10). Clinical attributes of the study frailty diagnosis, we applied the Edmonton Frail Scale (EFS) and participants are summarized in SI Appendix, Table S1. the Japanese version of the Montreal Cognitive Assessment First, we clinically evaluated whether the 19 participants were (MoCA-J) to evaluate cognitive aspects of frailty (16, 17). We frail, cognitively impaired, or hypomobile, according to EFS, show that antioxidants, amino acids, and metabolites related to MoCA-J, and TUG scores. Nine individuals (average age, 88.2 ± muscle or nitrogen metabolism link frailty to cognitive impairment 6.8 y) were diagnosed as frail (average EFS, 9.0 ± 1.2), while 10 and hypomobility. (average age, 80.5 ± 4.7 y) were not (average EFS, 4.7 ± 1.1) (SI Appendix, Table S1). According to the MoCA-J assessment, 15 Results and Discussion individuals displayed impaired cognition (average score; 19.3 ± Nineteen elderly participants, including 7 males and 12 females 3.8), while 4 were normal (average 27.0 ± 0.8). Regarding mo- with a mean age of 84.2 ± 6.9 y, were examined using the EFS, bility, 12 participants exhibited a prolonged TUG test (>10 s), the MoCA-J for cognitive function (17, 18), and the Timed Up & while 7 were normal (SI Appendix, Table S1). Both the MoCA-J Go (TUG) test for motor ability (19) (Fig. 1A). The EFS is an and TUG results were significantly diminished in frailty (Fig. 1B efficient diagnostic tool, comprising 10 questions to assess cog- and SI Appendix, Table S1). Significant correlations of EFS with nitive ability (clock-drawing test), mobility (TUG test), and MoCA-J, TUG, and functional independence test results fundamental daily activity, in which a score ≥7 indicates frailty (Fig. 1C and SI Appendix, Fig. S1) confirm that frailty involves (on a scale of 0 to 17) (16). It also covers domains related to simultaneously deteriorating physiological functions and social health status, functional independence, social support, medica- activities. tions, nutrition, mood, continence, and illness burden. The In this context, we performed untargeted analysis of 131 MoCA-J evaluates short-term memory, visuospatial ability, var- compounds in whole blood (Dataset S1). Our comprehensive ious executive functions, attention, concentration, working comparison of these
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